1. Field of the Invention
The present invention is directed to a process for inhibiting vascular proliferation in the retina by inducing posterior vitreous detachment in the eye of an animal. More, particularly invention relates to a process of introducing a composition into the eye, where the composition includes a collagen crosslinking agent and an active compound to induce posterior vitreous detachment in the eye to inhibit the effects of vitreous traction on the retina and other parts of the eye.
2. Background of the Invention
Vitreous traction is the attachment of vitreous fibrils to the basement membrane of the retina by cellular and molecular interactions between components of the vitreous and the inner limiting membrane. Fibronectin and laminin are extracellular glycoproteins which are known to be the most important components of the attaching mechanism for stabilizing the vitreoretinal attachment. The vitreous is a clear, proteinaceous material which fills the posterior of the eye between the lens and the retina. The vitreous is attached at its posterior face to the retina at the vitreoretinal junction along the inner limiting membrane. The vitreoretinal junction is a layer of basement membrane proximal to the vitreous.
The inner limiting membrane of the retina contains type I and type II collagen, laminin, fibronectin and glycoconjugates. These components have been found to bind collagen fibers between the vitreous and the inner limiting membrane.
Vitreous traction is recognized as a serious and potentially blinding complication in a number of vitreoretinal diseases following vitreoretinal surgery. An important aspect of most vitreoretinal surgery is to relieve the vitreous traction. Improvements have been made in mechanical vitrectomy techniques and instrumentation. However, the complete removal of the cortical vitreous from the retinal surface continues to be a difficult task. In some vitreoretinal proliferative disorders, surgical removal of the cortical vitreous can result in retinal break formation or bleeding from traction on retinal blood vessels.
Numerous studies have been conducted in attempts to develop a chemical system to separate the vitreoretinal interface without damage to the retina. These studies typically evaluate the vitreoretinal interface and have devised various pharmacological methods for inducing a traumatic separation between the vitreous and the retina. Intraoperative complications, such as retinal tears and hemorrhage can occur during surgical hyaloidectomy.
A number of enzymes and chemical substances have been used in attempts to induce posterior vitreous detachment. For example, chondroitinase did not show any activity but both hyaluronidase and Alpha-chymotrypsin caused posterior vitreous detachment. However, these enzymes produced peripapillary and vitreous hemorrhage in these eyes. Dispase, hyaluronidase, Alpha-chymotrypsin, collagenase, chondroitinase, and expansile gas are pharmacological agents used to induce PVD. Dispase has been used in human and porcine cadaver eyes to separate the attachment of the posterior hyaloid from the inner limiting membrane. Dispase induced posterior vitreous detachment with minor morphologic changes in the inner retina. However, dispase, at low concentrations of 0.05-0.07 U, can cause proliferative vitreoretinopathy in 94% of cases up to 21 days after intravitreal injection. Doses equal to or higher than 0.05 U dispase can cause histologic epiretinal cellular membranes in all animals and 25% to 50% cataract formation which is related to dispase concentration. Some toxicity to the inner layer of the retina 15 minutes after injection of dispase has been reported, in spite of inducing posterior vitreous detachment. Intravitreal injection of hyaluronidase induced PVD in rabbits. The probable mechanism of inducing posterior vitreous detachment using hyaluronidase is vitreous liquefaction.
One study of a pharmacological method of inducing posterior vitreous detachment is described by Verstraeten et al., Arch. Ophthalmol., Vol. 111, Jun. 1993. This study evaluated the effectiveness of plasmin, which is a serine protease, in cleaning the vitreoretinal interface between the posterior vitreous cortex and the internal limiting membrane. The results showed some vitreous detachment and the presence of inflammatory cells. Other studies reported the application of plasmin in the vitreous in pediatric macular hole cases. A less traumatic separation of the vitreous from the retina and optic nerve head was induced by the injection of plasmin intravitreally immediately prior to vitrectomy. Plasmin and a plasminogen activator were evaluated for their effect on the basement membrane where plasmin was shown to be effective in degrading laminin and fibronectin which are found at the vitreoretinal junction and play an important role in vitreoretinal attachment. These processes did not however, produce complete posterior vitreous detachment.
Another example of efforts to induce posterior vitreous detachment is disclosed in U.S. Pat. No. 5,722,428 to Kaplan et al. In this process dispase is selected to specifically cleave type IV collagen and fibronectin. The dispase is injected into the eye to promote posterior vitreous detachment. This process was shown to be ineffective in inducing complete vitreous detachment.
Accordingly, there is a continuing need for an effective process for inducing total or complete posterior vitreous detachment.
The present invention is directed to a composition and process for inhibiting the effects of vitreous contraction by inducing posterior vitreous detachment in the eye. More particularly, the invention is directed to a process of introducing a compound into the eye to induce crosslinking of the vitreous and to induce posterior vitreous detachment and inhibit the effects of vitreous traction on the retina.
Accordingly, a primary aspect of the invention is to provide a composition and process for inducing partial or complete posterior vitreous detachment that is efficient and effective to prevent or reduce the effects of vitreous contraction in the eye before the onset of complications from proliferative disorders.
Another aspect of the invention is to provide a composition and process for inducing crosslinking of the vitreous and for inducing substantially complete posterior vitreous detachment of the vitreous from the inner limiting membrane of the retina.
Still another aspect of the invention is to provide preventative or prophylactic processes by introducing a composition into the eye of a patient at risk of developing proliferative complications before the complications occur, where the composition includes plasminogen, a plasminogen activator and a collagen crosslinking agent.
A further aspect of the invention is to provide a process of inducing posterior vitreous detachment substantially without intraocular inflammation, electroretinography abnormalities or histologic abnormalities and without requiring a removal of the vitreous.
Another aspect of the invention is to provide a method and composition for crosslinking the vitreous and inducing posterior vitreous traction to separate the posterior hyaloid of the vitreous from the retina where the composition includes recombinant urokinase, recombinant plasminogen and glucose.
A further aspect of the invention is to provide a composition and process for dissolving fibrin, fibronectin and blood clots in the vitreous of the eye.
Another aspect of the invention is to provide a method and composition for inhibiting retinal tears and hemorrhage by introducing a composition into the eye where the composition includes plasminogen and a plasminogen activator without removing the vitreous from the eye.
A further aspect of the invention is to inject an expanding gas into the vitreous to compress the vitreous against the retina and thereafter injecting a composition into the eye to induce posterior vitreous detachment, where the composition comprises plasminogen, a plasminogen activator, and a collagen crosslinking agent.
Still another aspect of the invention is to provide a method of introducing a composition containing a collagen cross linking agent into the eye to cross link the collagen in the vitreous.
The aspects of the invention are basically attained by providing a process for inhibiting vascular proliferation in the eye and preventing or inhibiting retinal hemorrhaging, retinal tears and retinal detachment in the eye of a patient caused by vitreous contraction, said process comprising the steps of: introducing a composition into the vitreous of the eye of a patient in need thereof in an amount effective to prevent or inhibit retinal hemorrhaging, retinal tears and retinal detachment. The composition comprises a pharmaceutically acceptable carrier, a collagen crosslinking agent, plasminogen and a plasminogen activator. The composition is introduced into the vitreous in an amount to induce crosslinking of collagen in the vitreous and to induce separation of posterior hyaloid from the inner limiting membrane in the eye. Each of the components of the composition is introduced into the eye in a non-toxic amount substantially without inflammation.
The aspects of the invention are further attained by providing a composition for inhibiting vascular proliferation comprising plasminogen and a plasminogen activator enzyme in an amount sufficient to convert the plasminogen to plasmin and a collagen crosslinking agent. The plasminogen and plasminogen activator are present in amounts to induce substantially complete posterior vitreous detachment from the retina without causing inflammation. The crosslinking agent is included in an amount sufficient to crosslink the collagen in the vitreous and separate the vitreous from the inner limiting membrane.
The aspects of the invention are also attained by providing a process for dissolving fibrin in the vitreous, comprising introducing a composition into the vitreous of the eye in an effective amount to dissolve blood clots present in the vitreous. The composition comprises a mixture of plasminogen, a plasminogen activator enzyme and an ophthalmologically acceptable carrier.
The aspects of the invention are further attained by providing a process for inhibiting vascular proliferation in the eye of a patient which comprises the step of introducing an effective amount of a composition into the vitreous of the eye for sufficient time to induce posterior vitreous detachment. The composition comprises plasminogen and at least one active compound selected from the group consisting of urokinase, streptokinase, chondroitinase, tissue plasminogen activator, pro-urokinase, retavase, metaloproteinase, and thermolysin.
The aspects of the invention are still further attained by providing a process for preventing or inhibiting retinal hemorrhaging, retinal tears and retinal detachment in the eye caused by vitreous contraction. The process comprises the step of injecting a composition into the vitreous of the eye in an effective amount to induce posterior vitreous detachment in the eye. The composition comprises a pharmaceutically acceptable carrier, a collagen crosslinking agent, plasminogen and at least one active compound selected from the group consisting of urokinase, chondroitinase, pro-urokinase, tissue plasminogen activator, retavise, thermolysin, streptokinase, xcex1-thrombin, dipase, and transglutaminase.
The aspects of the invention are also attained by providing a composition for inducing posterior vitreous detachment in the eye of an animal and dissolving blood clots in the vitreous which comprises plasminogen, and a plasminogen activator enzyme in an amount sufficient to convert the plasminogen to plasmin where the plasminogen activator enzyme is selected from the group consisting of chondroitinase, pro-urokinase, tissue plasminogen activator, streptokinase, metaloproteinase, thermolysin, transglutaminase, and mixtures thereof. The plasminogen and plasminogen activator are present in amounts to induce posterior vitreous detachment from the retina without causing inflammation of the retina.
The aspects of the invention are still further attained by providing a process for dissolving fibrin in the vitreous of an eye comprising the steps of introducing a composition into the vitreous of the eye in an effective amount to dissolve fibrin present in the vitreous. The composition comprises a mixture of plasminogen, a plasminogen activator enzyme and an ophthalmologically acceptable carrier, and dissolving the fibrin in the vitreous.
Other aspects, advantages and salient features of the present invention will become apparent from the following detailed description, which, taken in conjunction with the annexed drawings, discloses preferred embodiments of the invention.